(1) Field of the Invention
This invention relates to novel pyrrolo[2,1-c]-[1,4]benzodiazepin-5-one compounds having antibacterial and antitumor activity and to their production by fermentation of a new microorganism.
(2) Description of the Prior Art
The antitumor antibiotics of the present invention are new members of the anthramycin-neothramycin group of antibiotics.
The antitumor antibiotics, neothramycin A and neothramycin B, are disclosed in J. Antibiotics 29(1): 93-96 (1976) and J. Antibiotics 30(4): 340-343 (1977) as having the structures
______________________________________ ##STR1## R.sub.1 R.sub.2 ______________________________________ neothramycin A H OH neothramycin B OH H ______________________________________
The antibiotic BBM-2040B of the present invention may be structurally differentiated from the neothramycins in the position of its hydroxyl group.
The diastereoisomers of BBM-2040A and B of the present invention have been disclosed in Symposium Papers of the 24th Symposium on the Chemistry of Natural Products (Osaka, Japan, Oct. 13-16, 1981): Paper #72, pp. 552-559. Compounds 31b and 32b in this paper have the structures ##STR2## and may be differentiated from BBM-2040A and B of the present invention in the configuration of the C-2 hydroxy group, i.e. BBM-2040A and B have the C-2 hydroxy group in the .alpha.-configuration while the corresponding 31b and 32b diastereoisomers have the .beta.-configuration at the C-2 hydroxy group. The present inventors have found that the .beta.-hydroxy isomers described in the reference are essentially devoid of antitumor activity in the P388 mouse leukemia test while the .alpha.-hydroxy isomers claimed in the present application have a marked activity against P388 mouse leukemia in this same screening test.
The antitumor antibiotic, tomaymycin, is disclosed in J. Antibiotics 25(8): 437-444 (1972) and Chem. Pharm. Bull 19(11): 2289-2293 (1971) as being obtained by fermentation of Streptomyces achromogenes var. tomaymyceticus. Tomaymycin, which has the structure ##STR3## may be differentiated from BBM-2040A by the presence of the ethylidene group at the C-2 position.
The antitumor antibiotic, pretomaymycin, is disclosed in J. Antibiotics 25: 437 (1972) as having the structure ##STR4## Pretomaymycin may be differentiated from BBM-2040B by the ethylidene group at the C-2 position.
The antitumor antibiotic, oxotomaymycin, having the formula ##STR5## is disclosed in Chem. Pharm. Bull 19: 2289 (1971). Oxotomaymycin differs from the BBM-2040 antibiotics in the presence of the 2-ethylidene group and the presence of the carbonyl group at C-11.
Among the members of the anthramycin group of antitumor antibiotics are anthramycin having the formula ##STR6## which is disclosed in J. Am. Chem. Soc. 87: 5791 (1965), mazethramycin having the formula ##STR7## which is disclosed in J. Antibiotics 33(6): 665-667 (1980) and sibiromycin of the formula ##STR8## which is disclosed in J. Antibiotics 27(11): 866-873 (1974) and J. Antibiotics 25(11): 668-673 (1972).
An extensive comparison of anthramycin, tomaymycin and sibiromycin is found in J. Antibiotics 30(5): 349-370 (1977).